Chromosomal microarray (CMA) has emerged as a robust tool for identifying microdeletions and microduplications, termed copy number variants (CNVs). Nevertheless, data regarding its utility in different patient populations with developmental delay (DD), dysmorphic features (DF) and congenital anomalies (CA), is a matter of dense debate. Although regions of homozygosity (ROH) are not diagnostic of a specific condition, they may have pathogenic implications. Certain CNVs and ROH have ethnically specific occurrences and frequencies. We aimed to determine whether CMA testing offers additional diagnostic information over classical cytogenetics for identifying genomic imbalances in a pediatric cohort with idiopathic DD, DF, or CA. One hundred sixty-nine patients were offered cytogenetics and CMA simultaneously for etiological diagnosis of DD (n = 67), DF (n = 52) and CA (n = 50). CMA could identify additional, clinically significant anomalies as compared with cytogenetics. CMA detected 61 CNVs [21 (34.4%) pathogenic CNVs, 37 (60.7%) variants of uncertain clinical significance and 3 (4.9%) benign CNVs] in 44 patients. CMA identified one or more ROH in 116/169 (68.6%) patients. When considering pathogenic CNVs and aneuploidies as positive findings, 9/169 (5.3%) received a genetic diagnosis from cytogenetics, while 25/169 (14.8%) could have a genetic diagnosis from CMA. The identification of ROH was clinically significant in two cases (2/169), thereby, adding 1.2% to the diagnostic yield of CMA (16% vs. 5.3%, p < 0.001). CMA uncovers additional genetic diagnoses over cytogenetics, thereby, offering a much higher diagnostic yield. Our findings convincingly demonstrate the additive diagnostic value of clinically significant ROH identified during CMA testing, highlighting the need for careful clinical interpretation of these ROH.

中文翻译：

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在发育迟缓，畸形特征或先天性异常的儿童中，在染色体微阵列测试中鉴定出的纯合子区域的附加诊断产率。

染色体微阵列（CMA）已成为一种可靠的工具，可用于识别微缺失和微重复，称为拷贝数变异（CNV）。然而，关于其在具有发育延迟（DD），畸形特征（DF）和先天性异常（CA）的不同患者人群中的效用的数据，尚需进行激烈的辩论。尽管纯合子区域（ROH）不能诊断特定疾病，但它们可能具有致病性。某些CNV和ROH具有种族特定的发生和频率。我们旨在确定CMA测试是否能提供比经典细胞遗传学更多的诊断信息，以鉴定患有特发性DD，DF或CA的小儿队列中的基因组失衡。向169例患者同时提供细胞遗传学和CMA诊断DD（n  = 67），DF（n  = 52）和CA（n  = 50）。与细胞遗传学相比，CMA可以发现其他具有临床意义的异常。CMA在44例患者中检测到61例CNV [21例（34.4％）致病性CNV，37例（60.7％）临床意义不确定的变异和3例（4.9％）良性CNV]。CMA在116/169（68.6％）患者中发现了一种或多种ROH。当将致病性CNV和非整倍性视为阳性发现时，9/169（5.3％）从细胞遗传学获得了基因诊断，而25/169（14.8％）可能从CMA获得了遗传诊断。在2例病例中（2/169），ROH的鉴定具有临床意义，因此，CMA的诊断率增加了1.2％（16％对5.3％，p <0.001）。CMA发现了除细胞遗传学之外的其他遗传诊断方法，从而提供了更高的诊断率。我们的发现令人信服地证明了在CMA测试过程中鉴定出的具有临床意义的ROH的附加诊断价值，突出表明需要对这些ROH进行仔细的临床解释。